Melinda Morrell, a graduate in medicine from the University of Manchester,  reports on the human epigenome project.  

Since the Human Genome Project was completed in April 2003, genetics has played an increasingly important role in the diagnosis, monitoring and treatment of disease.  By studying the sequential variations in genomes of different individuals, scientists are identifying the genes responsible for many of today’s common diseases such as hypertension, diabetes and cancer.  However, as the genetic onion is unravelled, something mysterious is found lurking within…Epigenetics…the study of heritable changes in gene function that occur without change to the sequence of DNA…the study of little on-off switches on our genes. The most recognised mechanism to date is DNA methylation- adding methyl groups to the cytosine bases which can silence or activate the gene.  Although recognised as an important mechanism in normal cell growth the consequences of some of these gene switches has also been shown to be a major causative factor of a wide variety of human diseases. 

Ever wondered why identical twins aren’t exactly identical if they have the same genes?  Why we can clone an embryo but not an adult?  Or why we share two thirds of our genes with a nematode?

Only 2% of our DNA codes for proteins and until recently the rest was considered as junk.  Humans seemed to have accumulated more junk than any other species.  Now we know that this junk or non-coding DNA is actually very useful in epigenetic processes even though it doesn’t translate into proteins (a revelation that undermines the central dogma that scientists had previously agreed upon that DNA merely acts to encode proteins and that only proteins do the real work of biology).  Infact, epigenetic changes to our genes, assisted by non-coding DNA are just as important as genetic changes in coding DNA in determining what we look like, how we think and what diseases we are going to get!    Whats more, these epigenetic changes, which occur throughout our lives, in response to what we eat, how we live and how much love our mothers gave us can be passed on to our children and their children etc…but in contrast to genetic changes, they are reversible!

But surely everyone knows that giraffe’s necks didn’t just get longer because they had to stretch to reach the treetops, as Lamarck had suggested?  We agreed with Darwin that we evolved due to genetic mutations in germ line cells that gave us survival advantages over competing species.  Now we are saying that characteristics can be acquired during life and we pass them on to our children?

Yes, and all at the flick of a switch!  Researchers found that baby rats that were not licked by their mums-a rodents form of nurturing-produced more stress hormones as adults due to the flick of a switch!  This was because they had switched off their gene for the glucocorticoid receptor in their brains, which normally controls the amount of stress hormone releases by the adrenal glands.  This effect was then reversed by injecting a chemical into their brains which could switch the gene back on!

Many more possible gene switches have been found in mice and rats with evidence to show that the epigenetic slate isn’t wiped clean with each generation.  If just one generation of rats are given a drug called alloxan, which decreases the body’s sensitivity to insulin, then their offspring and their offspring’s offspring will have diabetes.  If mice are exposed to high doses of morphine then the damage to their nervous systems will persist in their descendants.  And if a rat is given a single injection of thyroxine, then not only will that rat have a permanently depressed level of thyroid stimulating hormone but many of the rats of subsequent generations will too.

The evidence extends to humans as well.  Dutch women who went hungry in the Second World War gave birth to small babies, but their children also had small babies even though they had enough to eat.  We have known about the Barker hypothesis since around the early 1990s, which proposed that starved mothers “teach” their children to be efficient at conserving glucose predisposing them to the so-called metabolic syndrome. This tells us that nutrition in utero is largely responsible for our epigenetic programming and that under nutrition in one generation could explain the rise in obesity, heart disease and diabetes in the next!  It’s a far cry from the popular cultural view that lifestyle changes are the be all and end all determinants of good, or poor health - that everything boils down to personal decision making.  This is not to say that we are pre-programmed to develop disease and there is nothing we can do about it either.  We still think our lifestyle affects our chances of getting diseases-more than ever-because chemicals in our environment can trigger epigenetic switches!  The small task faced by scientists now is working out exactly what chemicals trigger exactly what switches in exactly what diseases!

Cancer Research

Epigenetics has already revolutionised cancer research with some very promising results.  Remember that there are two copies of every gene, one maternal and one paternal copy.  Therefore in order to switch a gene off, both copies would have to be silenced.  This is a lot easier if one copy of a gene has already been switched off early in embryonic development- an imprinted gene.  So far about 100 imprinted genes have been identified in humans, many of which are highly active in the brain.  If an imprinted gene also happens to be a tumour suppressor gene then loss of function becomes more likely as one copy has already been inactivated.  Such imprinted genes have been identified as contributing to a variety of familial and childhood cancers including neuroblastomas, acute myeloid leukaemia, Wilms tumours, rhabdomyosarcoma, paraganglioma, oesophageal cancer, follicular thyroid cancer and breast cancer.              

The battle of the sexes (at the molecular level)

The existence of these unusual imprinted genes is subject to much debate since they are potentially life threatening and yet have withstood evolutionary forces.  The best proposed theory to explain this phenomenon is the conflict theory where mum and dad are in disagreement about the supply of mum’s resources to her foetus.  Mum wants smaller babies to conserve her resources but dad wants big bouncy babies that are more likely to survive to pass on his genes.  Dad switches on his copy of the gene for Insulin-Like Growth Factor 2 (IGF2), a protein that makes big babies.  Meanwhile, mum switches on the IGF2 Receptor (IGF2R) gene so when IGF2 is trying to make her babies grow big and steal all her resources she can mop it up with IGF2R.  The truth is women are selfish, and have every right to be!  Yes, mum does all the hard work, carries us for 9 months, feeds us all the milk we need and looks after us while dads out doing the hunting…she’s so caring right?  The truth is given half the chance she would be out doing the hunting…so, why doesn’t she?  The reason…men have messed with their head!  Yes really!!!  Another imprinted gene called Mest which controls mothering behaviour has been switched on in the female brain by their fathers!

It seems mum and dads fighting doesn’t stop at deciding how big they want us to be but also how clever we are as well.  Areas of the brain responsible for complex thought are packed with cells containing two copies of maternal genes.  This is consistent with the fact that silencing of maternal imprinted genes in Angelman syndrome is associated with mental retardation.  Cells containing two copies of paternal genes tend to accumulate in the hypothalamus, responsible for basic functions such as temperature regulation, sexual function and feeding.  This is consistent with the silencing of paternal imprinted genes in Prader Willi syndrome is associated with an insatiable appetite and compulsive desire to obtain food to the point of retrieving it from dustbins or eating frozen raw meat.  Ongoing research has suggested a role for imprinted genes in a wide variety of common mental disorders such as autism, Alzheimers disease, schizophrenia and depression.

The Human Epigenome Project has begun

There is enormous potential for epigenetic medicine as we are beginning to find out.  Therapeutic reversal of epigenetic inactivation is already undergoing clinical trials in cancer research.  Therefore, the Human Epigenome Project was set up by an international collaboration which aims to identify and catalogue all of the DNA methylation patterns across the human genome and identify which ones are associated with disease.  The future of epigenotyping is so near and yet so much more ambitious than genotyping due to the interplay between environment and genes being so varied and volatile.  This is what makes the Human Epigenome Project so exciting as we can only begin to imagine the possibilities that it could bring for the future of medicine.

Melinda Morrell

References

1.            Egger G, Liang G, Aparicio A, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457-63

2.            Pray LA. Epigenetics: genome, meet your environment. The Scientist 2004.  (cited 21/06/07)

3.            Sapolsky RM. Mothering style and methylation.  Nature Neuroscience 2004; 7:791-792

4.            Weaver I et al. Epigenetic programming by maternal behaviour.  Nature Neuroscience 2004; 7:847-854

5.            Vines G. Hidden Inheritance.  New Scientist 1998; 2162:27-30

6.            Lumey LH.  Decreased birthweights in infants after maternal in utero exposure to the Dutch famine of 1944-1945. Paediatr Perinat Ep 1992; 6: 240-53

7.            Lumey LH.  Glucose tolerance in adults after prenatal exposure to famine.  Lancet 2001; 357(9254):472-3

8.            Corliss J.  Imprinted Genes Play Role, Change Rules in Cancer. JNCI 1993; 85: 1272-1274

9.            Niemitz E.  Milestone 15- Are You My Mother?  Nature Milestones in Gene Expression 2005

10.        Esteller M. The necessity of a human epigenome project.  Carcinogenesis 2006; 27:1121-1125.

11.        Hunter P.  The silence of genes.  Is genomic imprinting the software of evolution or just a battleground for gender conflict?  Nature 2007; 5:441-443

12.        Curley J.  Imprinting and Behaviour. In: Encyclopaedia of Genetics, Genomics, Proteomics and Bioinformatics. New York (NY): John Wiley & Sons, Ltd; 2005

13.        Brena RM, Huang THM, Plass C.  Toward a human epigenome. Nature Genetics 2006; 38:1359-1360

14.        Human Epigenome Project (Online) Available from: URL: www.epigenome.org (2006?) (cited 21/06/07)